R T Dorr1, K Snead, J D Liddil. 1. The University of Arizona College of Medicine, Department of Pharmacology, Tucson, Arizona, USA.
Abstract
BACKGROUND: THe antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS: Dehaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 x days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 degrees C or heating to 43-44 degrees C for 30 minutes after ID paclitaxel. RESULTS: Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P<0.05 by analysis of variance). None of the topical adjuvants or other ID adjuvants significantly reduced paclitaxel-induced skin ulcers in the mice. CONCLUSIONS: Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.
BACKGROUND: THe antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS: Dehaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 x days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 degrees C or heating to 43-44 degrees C for 30 minutes after ID paclitaxel. RESULTS: Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P<0.05 by analysis of variance). None of the topical adjuvants or other ID adjuvants significantly reduced paclitaxel-induced skin ulcers in the mice. CONCLUSIONS:Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.
Authors: Thomas Stahnke; Stefan Siewert; Thomas Reske; Wolfram Schmidt; Klaus-Peter Schmitz; Niels Grabow; Rudolf F Guthoff; Andreas Wree Journal: Biosci Rep Date: 2018-08-31 Impact factor: 3.840